Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Claims 1-34, 42-53 were cancelled, claims 39, 41, 56-63 were amended and claims 35-41 and 54-63 are pending in the instant application.
Election/Restrictions
Applicant elected without traverse SEQ ID NO:209 as the FN3 domain, siRNA as the agent of interest and muscle cell as the cell in the response filed November 19, 2025. After further review, the election of species is withdrawn.
Claims 35-41, 54-63 are examined on the merits of this office action.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 35-41, 54-63 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for delivery of siRNA or antisense oligonucleotides to CD71-expressing peripheral tissues (e.g. muscle, heart) using certain CD71 binding FN3 domains, the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
To comply with the enablement requirements of 35 U.S.C. §112, first paragraph, a specification must adequately teach how to make and how to use a claimed invention throughout its scope, without undue experimentation. Plant Genetic Systems N.V. v. DeKalb Genetics Corp., 315 F.3d 1335, 1339, 65 USPQ2d 1452, 1455 (Fed. Cir. 2003). There are a variety of factors which may be considered in determining whether a disclosure would require undue experimentation. These factors include: (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The Nature of the Invention/ The breadth of the claims
Claim 35 recites a method of delivering an agent of interest to a CD71 positive cell by contacting the cell with the agent of interest coupled to an FN3 domain that binds to CD71, wherein the FN3 domain comprise an amino acid sequence selected from a large genus including SEQ ID Nos:1-7, 10, 12-208, 210-219, 221-272, 292-299 or 304-306. Dependent claim further broaden the scope of the invention by reciting various agents of interest (e.g. chemotherapeutic agents, toxins, nucleic acids, siRNA, DNA molecules, etc.) and by reciting delivery to particular cell types including brain cells or cell inside of a blood brain barrier (claim 41). Although the specification provides certain examples relating FN3 domains that bind CD71 and describes conjugation of FN3 domains to nucleic acids, the disclosure does not provide sufficient guidance to enable the full scope of the claimed invention, particularly with respect to the breadth of FN3 sequence genus and delivery to any cells including those within the blood brain barrier. The claims are broad. Claim 35 encompasses FN3 domains comprising amino acid sequences selected from a large genus of sequences including hundreds of distinct SEQ ID nos. IN addition, the claims encompass coupling of these FN3 domains to a wide variety of agents of interest. Furthermore, claim 41 extends to scope of the method to brain cells or cells located within the blood brain barrier, thereby encompassing delivery of such agents into the CNS. The breadth of the claim substantially exceeds the limited number of embodiments described in the specification. Delivery of macromolecular therapeutic agents into specific tissues, particularly across the BBB, is recognized in the art as technically challenging and biologically complex. Transport of large biomolecules such as proteins, nucleic acids, and conjugates across the BBB in generally unpredictable and depends on numerous structural and biological factors.
The State of the Prior Art and the predictability or unpredictability of the art
The specification itself acknowledges that the blood brain barrier prevents most macromolecules from entering the brain (see e.g. paragraph 0263). The art generally recognizes that delivery of macromolecules across the BBB is difficult and often requires specialized transport mechanisms (see Su et al). Thus, the relevant field is one in which success is not readily predictable.
The field of protein mediated delivery of therapeutic agents, particularly across the blood brain barrier, is considered highly unpredictable. Small changes in protein sequence or structure can significantly affect receptor binding, trafficking, internalization, and tissue distribution. Accordingly, identifying functional variants within the large claimed sequence genus that successfully perform the claimed delivery functions would require significant experimentation.
The Relative Skill of Those in the Art
A person of ordinary skill in the art would likely have training in molecular biology, protein engineering, and drug delivery systems. However, even skilled practioners would require substantial experimentation to identify FN3 domain variants within the broad claimed genus that successfully deliver a variety of agents of interest to the claimed cells, particularly across the Blood brain barrier.
Amount of Guidance/ the Presence or Absence of Working Examples
The specification provides limited guidance for practicing the invention across the full scope of the claims. While the specification describes methods for generating and selecting FN3 domains that bind CD71 and provides general conjugation strategies, it does not provide detailed guidance enabling one of ordinary skill in the art to determine which of the many claimed FN3 variants would successfully deliver various agents to all claimed cell types, including brain cells or cells located within the BBB. The specification includes examples demonstrating FN3 domain binding to CD71 and conjugation of FN3 domains to siRNA constructs. However, the working examples primarily demonstrate gene knockdown in peripheral tissues such as skeletal muscle and heart in mice and cynomolgus monkeys (see e.g., paragraph 0297-0306). The specification does not provide working examples demonstrating delivery of agents across the blood brain barrier or delivery to brain cells. Thus, the disclosure does not demonstrate that the claimed methods are operable across the full scope of the claims.
The Quantity of Experimentation Necessary
Given the large number of claimed FN3 sequences, the variety of possible agents of interest, and the additional requirement delivering such agents to any cells including cells located within the BBB, a person of ordinary skill in the art would need to engage in substantial screening and experimentation to identify functional combinations that achieve the claimed results.
Therefore, in view of the Wands factors, the claims require undue experimentation to use the full scope of the claimed invention.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim(s) 59 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 59 recites “the antisense molecule”; however, the claims do not previously introduce an “antisense molecule”. Claim 55 recites an siRNA molecule comprising a sense strand and an antisense strand. Therefore, the proper antecedent basis appears to be “the antisense strand”, not “the antisense molecule”. Accordingly, the metes and bounds to claim 59 are unclear.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 35-41 and 54-63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 8, 16, 18, 20-22, 24-32 of copending Application No. 18/863539(reference application) in view of Brezksi (US20190127444). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A method of delivering an agent of interest to a CD71 positive cell, the method comprising contacting the cell with the agent of interest coupled to an FN3 domain that binds to CD71, wherein the FN3 domain comprises an amino acid sequence of SEQ ID NO: 209, 1-7, 10, 12-208, 210-219, 221-272, 292-299, or 304-306” (claim 35). The instant application further claims wherein the agent of interest is siRNA molecule (claim 56-58); antisense molecule (claim 59); wherein the cell is a muscle cell (claim 40); a cell in the BBB (claim 41); agent of interest is DNA molecule (claim 61); a further half life extending moiety (Claims 62-63).
Co-pending application 18/863539 claims “A method of reducing glycogen levels in a subject in need thereof, the method comprising administering a composition comprising one or more FN3 domains conjugated to an siRNA molecule, wherein the siRNA molecule comprises a sense strand and an antisense strand, and wherein the one or more FN3 domains comprises an FN3 domain that binds CD71 and the siRNA molecule targets GYS 1” (claim 1). Co-pending application 18/863539 further claims wherein the FN3 domain that binds CD71 comprises an amino acid sequence that is at least 87% identical to, or is identical to, a sequence of SEQ ID NO: 509, 708, 710, 273, 288-291, 301-310,312-508, 510-572,or 592-599 (see claim 24) which SEQ ID NO:509 is instant SEQ ID NO:209; delivery to a muscle cell (claim 32); administration to a subject would meet contacting the cell and would inherently contact a cell in the BBB. Thus, Co-pending application 18/863539 a method of using an FN3 domain of the instant claims coupled to a therapeutic, in particular siRNA and to the muscle thus meeting the limitations of the instant claims.
Co-pending application 18/863539 is silent to including a hall-life extending moiety.
However, Brezski teaches FN3 fusions comprising half-life extending moieties (see claim 1, paragraph 0013, paragraph 0093). It would have been obvious before the effective filing date of the claimed invention to conjugate or fuse a half-life extending moiety. One of ordinary skill in the art would have been motivated to do so because it would advantageous to increase the half life (prolong the activity of the therapeutic) in the method of Co-pending application 18/863539.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 35-38, 40-41 and 54-63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-34 of U.S. Patent No. 11628222 in view of Brezksi (US20190127444). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A method of delivering an agent of interest to a CD71 positive cell, the method comprising contacting the cell with the agent of interest coupled to an FN3 domain that binds to CD71, wherein the FN3 domain comprises an amino acid sequence of SEQ ID NO: 209, 1-7, 10, 12-208, 210-219, 221-272, 292-299, or 304-306” (claim 35). The instant application further claims wherein the agent of interest is siRNA molecule (claim 56-58); antisense molecule (claim 59); wherein the cell is a muscle cell (claim 40); a cell in the BBB (claim 41); agent of interest is DNA molecule (claim 61); a further half life extending moiety (Claims 62-63).
US Patent No. 11628222 (referred to as US Patent NO. ‘222) claims “A polypeptide comprising the amino acid sequence that is at least 90% identical to the amino acid sequence selected from the group consisting of SEQ ID NOs: 33-39, 41-62, 81-136, 138-186, 188-261, and 263-309, or at least 91% identical to the amino acid sequence selected from the group consisting of SEQ ID NOs: 40, 137, 187, and 262, or any combination thereof” (see claims 1 and 29). Several of the sequences overlap with the instant SEQ ID Nos. For example instant SEQ ID NO:12 is 254, 83 is 298 and 82 is 85 for example. US Patent No. 11628222 further claims wherein the peptide is conjugate to a therapeutic (claim 4) for delivery to a cell (see claim 29); siRNA as the therapeutic or DNA (see claim 7); cell across BBB (claim 30); muscle cell (claim 30).
US Patent NO. ‘222 is silent to including a hall-life extending moiety.
However, Brezski teaches FN3 fusions comprising half-life extending moieties (see claim 1, paragraph 0013, paragraph 0093). It would have been obvious before the effective filing date of the claimed invention to conjugate or fuse a half-life extending moiety. One of ordinary skill in the art would have been motivated to do so because it would advantageous to increase the half life (prolong the activity of the therapeutic) in the method of US Patent NO. ‘222.
Claims 35-41 and 54-63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 91, 98-130 of copending Application No. 19/039752(reference application) in view of Brezksi (US20190127444). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A method of delivering an agent of interest to a CD71 positive cell, the method comprising contacting the cell with the agent of interest coupled to an FN3 domain that binds to CD71, wherein the FN3 domain comprises an amino acid sequence of SEQ ID NO: 209, 1-7, 10, 12-208, 210-219, 221-272, 292-299, or 304-306” (claim 35). The instant application further claims wherein the agent of interest is siRNA molecule (claim 56-58); antisense molecule (claim 59); wherein the cell is a muscle cell (claim 40); a cell in the BBB (claim 41); agent of interest is DNA molecule (claim 61); a further half life extending moiety (Claims 62-63).
Co-pending application 19/039752 claims a method of treating a disease comprising administering FN3 coupled to siRNA (see claim 91). Co-pending application 19/039752 further claims wherein the cells over the BBB or muscle cell (claim 99); wherein the FN3 comprises SEQ ID Nos:519, 515 or 511 which are identical to instant SEQ ID Nos:219, 215 and 211; SEQ ID NO:509 which is instant SEQ ID NO:209 (Claim 117).
Co-pending application 19/039752 is silent to including a hall-life extending moiety.
However, Brezski teaches FN3 fusions comprising half-life extending moieties (see claim 1, paragraph 0013, paragraph 0093). It would have been obvious before the effective filing date of the claimed invention to conjugate or fuse a half-life extending moiety. One of ordinary skill in the art would have been motivated to do so because it would advantageous to increase the half life (prolong the activity of the therapeutic) in the method of Co-pending application 19/039752.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 35-41 and 54-63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20, 22-23, 25-26 of copending Application No. 18/301036 (reference application) in view of Brezksi (US20190127444). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A method of delivering an agent of interest to a CD71 positive cell, the method comprising contacting the cell with the agent of interest coupled to an FN3 domain that binds to CD71, wherein the FN3 domain comprises an amino acid sequence of SEQ ID NO: 209, 1-7, 10, 12-208, 210-219, 221-272, 292-299, or 304-306” (claim 35). The instant application further claims wherein the agent of interest is siRNA molecule (claim 56-58); antisense molecule (claim 59); wherein the cell is a muscle cell (claim 40); a cell in the BBB (claim 41); agent of interest is DNA molecule (claim 61); a further half life extending moiety (Claims 62-63).
Co-pending application 18/301036 claims a method of treating a disease comprising administering FN3 coupled to siRNA (see claim 1). Co-pending application 18/301036 further claims wherein the FN3 comprises SEQ ID Nos:519, 515 or 511 which are identical to instant SEQ ID Nos:219, 215 and 211 and 509 which is instant SEQ ID NO:209 (se claims 12-15); administration to a subject would meet contacting the cell and would inherently contact a cell in the BBB.
Co-pending application 18/301036 is silent to including a hall-life extending moiety.
However, Brezski teaches FN3 fusions comprising half-life extending moieties (see claim 1, paragraph 0013, paragraph 0093). It would have been obvious before the effective filing date of the claimed invention to conjugate or fuse a half-life extending moiety. One of ordinary skill in the art would have been motivated to do so because it would advantageous to increase the half life (prolong the activity of the therapeutic) in the method of Co-pending application 18/301036.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 35-41 and 54-63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 10-21, 23-25 of copending Application No. 18/490450 (reference application) in view of Brezksi (US20190127444). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A method of delivering an agent of interest to a CD71 positive cell, the method comprising contacting the cell with the agent of interest coupled to an FN3 domain that binds to CD71, wherein the FN3 domain comprises an amino acid sequence of SEQ ID NO: 209, 1-7, 10, 12-208, 210-219, 221-272, 292-299, or 304-306” (claim 35). The instant application further claims wherein the agent of interest is siRNA molecule (claim 56-58); antisense molecule (claim 59); wherein the cell is a muscle cell (claim 40); a cell in the BBB (claim 41); agent of interest is DNA molecule (claim 61); a further half life extending moiety (Claims 62-63).
Co-pending application 18/490540 claims a method of treating a disease comprising administering FN3 coupled to siRNA (see claim 1). Co-pending application 18/490450 further claims wherein the FN3 comprises SEQ ID Nos:570 which is identical to instant SEQ ID NO:209 (see claim21); administration to a subject would meet contacting the cell and would inherently contact a cell in the BBB.
Co-pending application 18/490540 is silent to including a hall-life extending moiety.
However, Brezski teaches FN3 fusions comprising half-life extending moieties (see claim 1, paragraph 0013, paragraph 0093). It would have been obvious before the effective filing date of the claimed invention to conjugate or fuse a half-life extending moiety. One of ordinary skill in the art would have been motivated to do so because it would advantageous to increase the half life (prolong the activity of the therapeutic) in the method of Co-pending application 18/490540.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Closest Prior art Made of Record
The closest prior art made of record is Torres (WO2015089073 A1). Torres teaches molecules comprising binding domains, wherein a binding domain comprises FN3 (see paragraph 019). The FN3 domain of Torres comprises a sequence that is 89.9% sequence identity to instant SEQ ID NO:10. Furthermore, Diem (US20180162929 A1) teaches of FN3 domains and conjugates thereof (see abstract). Diem teaches use of the FN3 domains for cellular delivery of therapeutic agents and half life extending moieties (see claims 3-5, 8-9). Diem teaches of an FN3 domain comprising 89.1% sequence similarity to instant SEQ ID NO:21 (See SEQ ID NO:153). Additionally, Diem (Protein Engineering, Design & Selection vol. 27 no. 10 pp. 419–429, 2014, cited in Applicant’s IDS) teaches of Centyrins which are based on FN3 domains (see abstract). Figure 3 shows sequences similar to the instant SEQ ID Nos (see Tencon25, mutants thereof). However, there is not teaching, suggestion, motivation or rationale to modify the sequences of the prior art to result in the sequences found in instant claim 35.
Conclusion
No claims are allowed.
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/ERINNE R DABKOWSKI/Examiner, Art Unit 1654